Preventing leprosy with retrospective active case finding combined with single-dose rifampicin for contacts in a low endemic setting: results of the Leprosy Post-Exposure Prophylaxis program in Cambodia

Post-exposure prophylaxis (PEP) with single-dose rifampicin (SDR) reduces the risk of developing leprosy among contacts of leprosy patients. Most evidence for the feasibility of the intervention is from highly endemic settings while low-endemic areas present unique challenges including reduced awareness of the disease among the population and in the health system, and the only sporadic occurrence of cases which together make defining any type of routine process challenging. We complemented the retrospective active case finding (RACF) approach with SDR administration to eligible contacts, and piloted the intervention across 31 operational districts in Cambodia. The aim was to demonstrate the feasibility of improving early case detection and administering SDR in a low endemic setting. The intervention focused on leprosy patients diagnosed since 2011 and was implemented between October 2016 - September 2019. The "drives" approach was employed to trace contacts: a trained team systematically contacted all eligible cases in a district, traced and screened contacts, and administered SDR. A total of 555 index patients were traced by the drive team, and 10,410 contacts in their household and 5 immediate neighbor houses listed. Among these contacts, 72.0% could be screened while most others were absent on the screening day. A total of 33 new leprosy cases were diagnosed and 6189 contacts received SDR (82.6% of the screened contacts). Sixty-one contacts refused SDR administration. We conclude that integrating PEP with SDR in RACF campaigns is feasible, and that this approach is appropriate in low resource and low endemic settings. Over time, evidence on whether or not the approach reduced leprosy transmission in Cambodia, may become clear

Elasticity Theory and Shape Transitions of Viral Shells

Recently, continuum elasticity theory has been applied to explain the shape transition of icosahedral viral capsids - single-protein-thick crystalline shells - from spherical to buckled/faceted as their radius increases through a critical value determined by the competition between stretching and bending energies of a closed 2D elastic network. In the present work we generalize this approach to capsids with non-icosahedral symmetries, e.g., spherocylindrical and conical shells. One key new physical ingredient is the role played by nonzero spontaneous curvature. Another is associated with the special way in which the energy of the twelve topologically-required five-fold sites depends on the background local curvature of the shell in which they are embedded. Systematic evaluation of these contributions leads to a shape phase diagram in which transitions are observed from icosahedral to spherocylindrical capsids as a function of the ratio of stretching to bending energies and of the spontaneous curvature of the 2D protein network. We find that the transition from icosahedral to spherocylindrical symmetry is continuous or weakly first-order near the onset of buckling, leading to extensive shape degeneracy. These results are discussed in the context of experimentally observed variations in the shapes of a variety of viral capsids.Comment: 53 pages, 17 figure

Effects of mechanical strain on thermal denaturation of DNA

As sections of a strand duplexed DNA denature when exposed to high temperature, the excess linking number is taken up by the undenatured portions of the molecule. The mechanical energy that arises because of the overwinding of the undenatured sections can, in principle, alter the nature of the thermal denaturation process. Assuming that the strains associated with this overwinding are not relieved, we find that a simple model of strain-altered melting leads to a suppression of the melting transition when the unaltered transition is continuous. When the melting transition is first order in the absence of strain associated with overwinding, the modification is to a third order phase transition.Comment: 4 pages, 5 figures, RevTe

Folding Langmuir Monolayers

The maximum pressure a two-dimensional surfactant monolayer is able to withstand is limited by the collapse instability towards formation of three-dimensional material. We propose a new description for reversible collapse based on a mathematical analogy between the formation of folds in surfactant monolayers and the formation of Griffith Cracks in solid plates under stress. The description, which is tested in a combined microscopy and rheology study of the collapse of a single-phase Langmuir monolayer of 2-hydroxy-tetracosanoic acid (2-OH TCA), provides a connection between the in-plane rheology of LM's and reversible folding

Rhythmogenic neuronal networks, pacemakers, and k-cores

Neuronal networks are controlled by a combination of the dynamics of individual neurons and the connectivity of the network that links them together. We study a minimal model of the preBotzinger complex, a small neuronal network that controls the breathing rhythm of mammals through periodic firing bursts. We show that the properties of a such a randomly connected network of identical excitatory neurons are fundamentally different from those of uniformly connected neuronal networks as described by mean-field theory. We show that (i) the connectivity properties of the networks determines the location of emergent pacemakers that trigger the firing bursts and (ii) that the collective desensitization that terminates the firing bursts is determined again by the network connectivity, through k-core clusters of neurons.Comment: 4+ pages, 4 figures, submitted to Phys. Rev. Let

Electrostatics and the Assembly of an RNA Virus

Electrostatic interactions play a central role in the assembly of single-stranded RNA viruses. Under physiological conditions of salinity and acidity, virus capsid assembly requires the presence of genomic material that is oppositely charged to the core proteins. In this paper we apply basic polymer physics and statistical mechanics methods to the self-assembly of a synthetic virus encapsidating generic polyelectrolyte molecules. We find that (i) the mean concentration of the encapsidated polyelectrolyte material depends on the surface charge density, the radius of the capsid, and the linear charge density of the polymer but neither on the salt concentration or the Kuhn length, (ii) the total charge of the capsid interior is equal but opposite to that of the empty capsid, a form of charge reversal. Unlike natural viruses, synthetic viruses are predicted not to be under an osmotic swelling pressure. The design condition that self-assembly only produces filled capsids is shown to coincide with the condition that the capsid surface charge exceeds the desorption threshold of polymer surface adsorption. We compare our results with studies on the self-assembly of both synthetic and natural viruses.Comment: 41 pages, 4 figure

The involvement of cancer patients in the four stages of decision-making preceding continuous sedation until death: A qualitative study

BACKGROUND: Involving patients in decision-making is considered to be particularly appropriate towards the end of life. Professional guidelines emphasize that the decision to initiate continuous sedation should be made in accordance with the wishes of the dying person and be preceded by their consent. AIM: To describe the decision-making process preceding continuous sedation until death with particular attention to the involvement of the person who is dying. DESIGN: Qualitative case studies using interviews. SETTING/PARTICIPANTS: Interviews with 26 physicians, 30 nurses and 24 relatives caring for 24 patients with cancer who received continuous sedation until death in Belgium, the United Kingdom and the Netherlands. RESULTS: We distinguished four stages of decision-making: initiation, information exchange, deliberation and the decision to start continuous sedation until death. There was wide variation in the role the patient had in the decision-making process. At one end of the spectrum (mostly in the United Kingdom), the physician discussed the possible use of sedation with the patient, but took the decision themselves. At the other end (mostly in Belgium and the Netherlands), the patient initiated the conversation and the physician's role was largely limited to evaluating if and when the medical criteria were met. CONCLUSION: Decision-making about continuous sedation until death goes through four stages and the involvement of the patient in the decision-making varies. Acknowledging the potential sensitivity of raising the issue of end-of-life sedation, we recommend building into clinical practice regular opportunities to discuss the goals and preferences of the person who is dying for their future medical treatment and care

Physicians' opinion and practice with the continuous use of sedatives in the last days of life

CONTEXT: There are few international studies about the continuous use of sedatives (CUS) in the last days of life. OBJECTIVES: We aim to describe the experiences and opinions regarding CUS of physicians caring for terminally ill patients in seven countries. METHODS: Questionnaire study about practices and experiences with CUS in the last days of life among physicians caring for terminally ill patients in Belgium (N=175), Germany (N=546), Italy (N=214), Japan (N=513), the Netherlands (N=829), United Kingdom (N=114) and Singapore (N=21). RESULTS: The overall response rate was 22%. Of the respondents, 88-99% reported that they had clinical experience of CUS in the last 12 months. More than 90% of respondents indicated that they mostly used midazolam for sedation. The use of sedatives to relieve suffering in the last days of life was considered acceptable in cases of physical suffering (87-99%). This percentage was lower but still substantial in cases of psycho-existential suffering in the absence of physical symptoms (45-88%). These percentages were lower when the prognosis was at least several weeks (22- 66% for physical suffering and 5-42% for psycho-existential suffering). Of the respondents, 10% or less agreed with the statement that CUS is unnecessary because suffering can be alleviated with other measures. A substantial proportion (41-95%) agreed with the statement that a competent patient with severe suffering has the right to demand the use of sedatives in the last days of life. CONCLUSION: Many respondents in our study considered CUS acceptable for the relief of physical and psycho-existential suffering in the last days of life. The acceptability was lower regarding CUS for psycho-existential suffering and regarding CUS for patients with a longer life expectancy. FUNDING: Ministry of Education, Culture, Sports, Science and Technology, Japan KEY MESSAGE: : This questionnaire study among physicians caring for terminally ill patients showed that many considered the continuous use of sedatives acceptable to relieve physical and psycho-existential suffering in the last days of life. Respondents' regarded the practice as less acceptable in patients with a longer life expectancy

Towards the reconstruction of the genome-scale metabolic model of Lactobacillus acidophilus La-14

Lactobacillus acidophilus is a probiotic lactic acid bacterium used in food and dietary supplements for many years. However, despite its importance for industrial development and recognized health-promoting effects, no genome-scale metabolic model has been reported. A GSM model for L. acidophilus La-14 was developed, accounting 494 genes and 783 reactions. A genome annotation was performed to identify the metabolic potential of the bacterium. The biomass composition was determined based on information available in literature and previously published models. The model was validated by comparing in silico simulations with experimental data, regarding the aerobic and anaerobic growth. The reconstruction of the metabolic model has confirmed the fastidious requirements of L. acidophilus for amino acids, fatty acids, and vitamins. This model can be used for a better understanding of the metabolism of this bacterium and identification of industrially desirable compounds.This study was performed under the scope of the project “BIODATA.PT – Portuguese Biological Data Network” (ref. LISBOA-01-0145-FEDER-022231), funded by FCT/MCTES, through national funds of PIDDAC, Fundo Europeu de Desenvolvimento Regional (FEDER), Programa Operacional de Competitividade e Internacionalização (POCI) and Programa Operacional Regional de Lisboa (Lisboa 2020).info:eu-repo/semantics/publishedVersio

Elliptical Galaxy Dynamics

A review of elliptical galaxy dynamics, with a focus on nonintegrable models. Topics covered include torus construction; modelling axisymmetric galaxies; triaxiality; collisionless relaxation; and collective instabilities.Comment: 97 Latex pages, 14 Postscript figures, uses aastex. To appear in Publications of the Astronomical Society of the Pacific, February 199